Acetylcholinesterase Inhibitors: Structure Based Design, Synthesis, Pharmacophore Modeling, and Virtual Screening

Acetylcholinesterase (AChE) is a main drug target, and its inhibitors have demonstrated functionality in the symptomatic treatment of Alzheimer’s disease (AD). In this study, a series of novel AChE inhibitors were designed and their inhibitory activity was evaluated with 2D quantitative structure–activity relationship (QSAR) studies using a training set of 20 known compounds for which IC₅₀ values had previously been determined. The QSAR model was calculated based on seven unique descriptors. Model validation was determined by predicting IC₅₀ values for a test set of 20 independent compounds with measured IC₅₀ values. A correlation analysis was carried out comparing the statistics of the measured IC₅₀ values with predicted ones. These selectivity-determining descriptors were interpreted graphically in terms of principal component analyses (PCA). A 3D pharmacophore model was also created based on the activity of the training set. In addition, absorption, distribution, metabolism, and excretion (ADME) descriptors were also determined to evaluate their pharmacokinetic properties. Finally, molecular docking of these novel molecules into the AChE binding domain indicated that three molecules (<b>6c</b>, <b>7c</b>, and <b>7h)</b> should have significantly higher affinities and solvation energies than the known standard drug donepezil. The docking studies of 2<i>H</i>-thiazolo­[3,2-<i>a</i>]­pyrimidines (<b>6a</b>–<b>6j</b>) and 5<i>H</i>-thiazolo­[3,2-<i>a</i>] pyrimidines (<b>7a</b>–<b>7j</b>) with human AChE have demonstrated that these ligands bind to the dual sites of the enzyme. Simple and ecofriendly syntheses and diastereomeric crystallizations of 2<i>H</i>-thiazolo [3,2-<i>a</i>]­pyrimidines and 5<i>H</i>-thiazolo­[3,2-<i>a</i>] pyrimidines are described. The solid-state structures for the HBr salts of compounds <b>6a</b>,<b> 6e</b>, <b>7a</b>, and <b>7i</b> have been determined using single-crystal X-ray diffraction techniques, and X-ray powder patterns were measured for the bulk solid remaining after solvent was removed from solutions containing <b>6a</b> and <b>7a</b>. These studies provide valuable insight for designing more potent and selective inhibitors for the treatment of AD